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  1. Article ; Online: RNA-Based Homologous Recombination Deficiency Signature Detects Homologous Recombination Deficiency-RNA+ Patients With and Without Homologous Recombination Repair Gene Pathogenic Alterations in Men With Prostate Cancer.

    Brown, Landon C / Zhu, Jason / Mauer, Elizabeth / Thiede, Stephanie N / Macera, Lisa / Stein, Michelle M / Taxter, Timothy / Raghavan, Derek / Burgess, Earle F

    JCO precision oncology

    2023  Volume 7, Page(s) e2300378

    Abstract: Purpose: Homologous recombination deficiency (HRD) is a well-described phenotype of some prostate cancers; however, current biomarkers for HRD are imperfect and rely on detection of single gene alterations in the homologous recombination repair (HRR) ... ...

    Abstract Purpose: Homologous recombination deficiency (HRD) is a well-described phenotype of some prostate cancers; however, current biomarkers for HRD are imperfect and rely on detection of single gene alterations in the homologous recombination repair (HRR) pathway, which may not capture the complexity of HRD biology. RNA signature-based methods of HRD identification present a potentially dynamic assessment of the HRD phenotype; however, its relationship with HRR gene alterations is not well characterized in prostate cancer.
    Methods: A HRD assay on the basis of an RNA signature associated with biallelic
    Results: In this cohort, of the 126 (13%) patients found to be HRD+ by RNA signature (HRD-RNA+), 100 (79%) had no coexisting HRR gene alteration. Among samples with biallelic
    Conclusion: Use of an RNA-based HRD signature significantly expands the fraction of patients with prostate cancer who may derive benefit from poly (ADP-ribose) polymerase inhibitors (PARPis) compared with using HRR gene mutations alone. Further studies are needed to evaluate functional HRD significance and inform future usage as a predictive biomarker for PARPi selection.
    MeSH term(s) Male ; Humans ; BRCA1 Protein/genetics ; Recombinational DNA Repair/genetics ; Homologous Recombination/genetics ; Retrospective Studies ; BRCA2 Protein/genetics ; Prostatic Neoplasms/genetics ; Poly(ADP-ribose) Polymerase Inhibitors
    Chemical Substances BRCA1 protein, human ; BRCA1 Protein ; BRCA2 protein, human ; BRCA2 Protein ; Poly(ADP-ribose) Polymerase Inhibitors
    Language English
    Publishing date 2023-06-14
    Publishing country United States
    Document type Journal Article
    ISSN 2473-4284
    ISSN (online) 2473-4284
    DOI 10.1200/PO.23.00378
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Comparison of the tumor immune microenvironment and checkpoint blockade biomarkers between stage III and IV non-small cell lung cancer.

    Gao, Yinjie / Stein, Michelle M / Kase, Matthew / Cummings, Amy L / Bharanikumar, Ramit / Lau, Denise / Garon, Edward B / Patel, Sandip P

    Cancer immunology, immunotherapy : CII

    2022  Volume 72, Issue 2, Page(s) 339–350

    Abstract: Background: Adjuvant immune checkpoint blockade (ICB) following chemoradiotherapy and adding ICB to chemotherapy have been key advances for stages III-IV non-small cell lung cancer (NSCLC) treatment. However, known biomarkers like PD-L1 are not ... ...

    Abstract Background: Adjuvant immune checkpoint blockade (ICB) following chemoradiotherapy and adding ICB to chemotherapy have been key advances for stages III-IV non-small cell lung cancer (NSCLC) treatment. However, known biomarkers like PD-L1 are not consistently indicative of ICB response. Other markers within the tumor immune microenvironment (TIME) may better reflect ICB response and/or resistance mechanisms, but an understanding of how TIMEs differ between stage III and IV NSCLC has not been explored.
    Methods: Real-world data from unresectable, stage III-IV, non-squamous, pretreatment NSCLCs (stage III n = 106, stage IV n = 285) were retrospectively analyzed. PD-L1 immunohistochemistry (IHC) was compared to CD274 gene expression. Then, differential gene expression levels, pathway enrichment, and immune infiltrate between stages were calculated from whole-transcriptome RNA-seq. Analyses were stratified by EGFR status.
    Results: PD-L1 IHC and CD274 expression in tumor cells were highly correlated (n = 295, P < 2.2e-16, ⍴ = 0.74). CTLA4 expression was significantly increased in stage III tumors (P = 1.32e-04), while no differences were observed for other ICB-related genes. Metabolic pathway activity was significantly enriched in stage IV tumors (P = 0.004), whereas several immune-related KEGG pathways were enriched in stage III. Stage IV tumors had significantly increased macrophage infiltration (P = 0.0214), and stage III tumors had a significantly higher proportion of CD4 + T cells (P = 0.017). CD4 + T cells were also relatively more abundant in EGFR-mutant tumors vs. wild-type (P = 0.0081).
    Conclusion: Directly comparing the TIMEs of stage III and IV NSCLC, these results carry implications for further studies of ICB response in non-resectable stage III NSCLC and guide further research of prognostic biomarkers and therapeutic targets.
    MeSH term(s) Humans ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Lung Neoplasms/drug therapy ; B7-H1 Antigen/metabolism ; Retrospective Studies ; Biomarkers ; Tumor Microenvironment ; Immune Checkpoint Inhibitors/therapeutic use ; ErbB Receptors ; Biomarkers, Tumor
    Chemical Substances B7-H1 Antigen ; Biomarkers ; Immune Checkpoint Inhibitors ; ErbB Receptors (EC 2.7.10.1) ; Biomarkers, Tumor
    Language English
    Publishing date 2022-07-26
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 195342-4
    ISSN 1432-0851 ; 0340-7004
    ISSN (online) 1432-0851
    ISSN 0340-7004
    DOI 10.1007/s00262-022-03252-y
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Effects of an FcγRIIA polymorphism on leukocyte gene expression and cytokine responses to anti-CD3 and anti-CD28 antibodies.

    Stein, Michelle M / Hrusch, Cara L / Sperling, Anne I / Ober, Carole

    Genes and immunity

    2018  Volume 20, Issue 6, Page(s) 462–472

    Abstract: The low affinity Fcγ receptor, FcγRIIA, harbors a common missense mutation, rs1801274 (G>A, Arg131His) that modifies binding affinity to human IgG2 and mouse IgG1 antibodies and is associated with increased risk of autoimmune disease. Despite the ... ...

    Abstract The low affinity Fcγ receptor, FcγRIIA, harbors a common missense mutation, rs1801274 (G>A, Arg131His) that modifies binding affinity to human IgG2 and mouse IgG1 antibodies and is associated with increased risk of autoimmune disease. Despite the important role of the Arg131His variant, little is understood about heterozygous genotype effects on global gene expression and cytokine production during an FcγR-dependent response. To address this gap in knowledge, we treated human whole-blood samples from 130 individuals with mouse IgG1 anti-CD3 and anti-CD28 antibodies and characterized the genome-wide gene expression profiles and cytokine production among individuals stratified by rs1801274 genotype. Our analysis revealed that the levels of four cytokines (IFNγ, IL-12, IL-2, TNFα) and global gene expression patterns differed between all three genotype classes. Surprisingly, the heterozygotes showed suboptimal T cell activation compared to cells from individuals homozygous for the higher-affinity FcγRIIA allele (GG; Arg/Arg). The results of this study demonstrate that IgG response varies among all rs1801274 genotype classes and results in profound differences in both cytokine responses and gene expression patterns in blood leukocytes. Because even heterozygotes showed dampened global responses, our data may provide insight into the heterogeneity of outcomes in cytokine release assays and immunotherapy efficacy.
    MeSH term(s) Adolescent ; Adult ; Aged ; Alleles ; Antibodies/pharmacology ; CD28 Antigens/antagonists & inhibitors ; CD28 Antigens/immunology ; CD3 Complex/antagonists & inhibitors ; CD3 Complex/immunology ; Child ; Genotype ; Heterozygote ; Homozygote ; Humans ; Interferon-gamma/blood ; Interferon-gamma/metabolism ; Interleukin-12/blood ; Interleukin-12/metabolism ; Interleukin-2/blood ; Interleukin-2/metabolism ; Leukocytes/immunology ; Leukocytes/metabolism ; Middle Aged ; Polymorphism, Genetic ; Receptors, IgG/genetics ; T-Lymphocytes/metabolism ; Transcriptome/immunology ; Tumor Necrosis Factor-alpha/blood ; Tumor Necrosis Factor-alpha/metabolism ; Young Adult
    Chemical Substances Antibodies ; CD28 Antigens ; CD3 Complex ; Fc gamma receptor IIA ; Interleukin-2 ; Receptors, IgG ; Tumor Necrosis Factor-alpha ; Interleukin-12 (187348-17-0) ; Interferon-gamma (82115-62-6)
    Language English
    Publishing date 2018-07-06
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2060566-3
    ISSN 1476-5470 ; 1466-4879
    ISSN (online) 1476-5470
    ISSN 1466-4879
    DOI 10.1038/s41435-018-0038-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Sex-specific differences in peripheral blood leukocyte transcriptional response to LPS are enriched for HLA region and X chromosome genes.

    Stein, Michelle M / Conery, Mitch / Magnaye, Kevin M / Clay, Selene M / Billstrand, Christine / Nicolae, Raluca / Naughton, Katherine / Ober, Carole / Thompson, Emma E

    Scientific reports

    2021  Volume 11, Issue 1, Page(s) 1107

    Abstract: Sex-specific differences in prevalence are well documented for many common, complex diseases, especially for immune-mediated diseases, yet the precise mechanisms through which factors associated with biological sex exert their effects throughout life are ...

    Abstract Sex-specific differences in prevalence are well documented for many common, complex diseases, especially for immune-mediated diseases, yet the precise mechanisms through which factors associated with biological sex exert their effects throughout life are not well understood. We interrogated sex-specific transcriptional responses of peripheral blood leukocytes (PBLs) to innate immune stimulation by lipopolysaccharide (LPS) in 46 male and 66 female members of the Hutterite community, who practice a communal lifestyle. We identified 1217 autosomal and 54 X-linked genes with sex-specific responses to LPS, as well as 71 autosomal and one X-linked sex-specific expression quantitative trait loci (eQTLs). Despite a similar proportion of the 15 HLA genes responding to LPS compared to all expressed autosomal genes, there was a significant over-representation of genes with sex by treatment interactions among HLA genes. We also observed an enrichment of sex-specific differentially expressed genes in response to LPS for X-linked genes compared to autosomal genes, suggesting that HLA and X-linked genes may disproportionately contribute to sex disparities in risk for immune-mediated diseases.
    MeSH term(s) Adolescent ; Adult ; Aged ; Aged, 80 and over ; Child ; Ethnic Groups ; Female ; Gene Expression Profiling ; Genes, MHC Class I ; Genes, MHC Class II ; Genes, X-Linked ; Humans ; Immunity, Innate ; Leukocytes/immunology ; Leukocytes/metabolism ; Lipopolysaccharides/immunology ; Male ; Middle Aged ; Quantitative Trait Loci ; Sex Characteristics ; Transcription, Genetic ; Young Adult
    Chemical Substances Lipopolysaccharides
    Language English
    Publishing date 2021-01-13
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-020-80145-z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Integration of tumor extrinsic and intrinsic features associates with immunotherapy response in non-small cell lung cancer.

    Lau, Denise / Khare, Sonal / Stein, Michelle M / Jain, Prerna / Gao, Yinjie / BenTaieb, Aicha / Rand, Tim A / Salahudeen, Ameen A / Khan, Aly A

    Nature communications

    2022  Volume 13, Issue 1, Page(s) 4053

    Abstract: The efficacy of immune checkpoint blockade (ICB) varies greatly among metastatic non-small cell lung cancer (NSCLC) patients. Loss of heterozygosity at the HLA-I locus (HLA-LOH) has been identified as an important immune escape mechanism. However, ... ...

    Abstract The efficacy of immune checkpoint blockade (ICB) varies greatly among metastatic non-small cell lung cancer (NSCLC) patients. Loss of heterozygosity at the HLA-I locus (HLA-LOH) has been identified as an important immune escape mechanism. However, despite HLA-I disruptions in their tumor, many patients have durable ICB responses. Here we seek to identify HLA-I-independent features associated with ICB response in NSCLC. We use single-cell profiling to identify tumor-infiltrating, clonally expanded CD4
    MeSH term(s) Biomarkers, Tumor/genetics ; CD8-Positive T-Lymphocytes ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/genetics ; Humans ; Immunotherapy ; Lung Neoplasms/drug therapy ; Lung Neoplasms/genetics
    Chemical Substances Biomarkers, Tumor
    Language English
    Publishing date 2022-07-13
    Publishing country England
    Document type Journal Article
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-022-31769-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Parent of origin gene expression in a founder population identifies two new candidate imprinted genes at known imprinted regions.

    Mozaffari, Sahar V / Stein, Michelle M / Magnaye, Kevin M / Nicolae, Dan L / Ober, Carole

    PloS one

    2018  Volume 13, Issue 9, Page(s) e0203906

    Abstract: Genomic imprinting is the phenomena that leads to silencing of one copy of a gene inherited from a specific parent. Mutations in imprinted regions have been involved in diseases showing parent of origin effects. Identifying genes with evidence of parent ... ...

    Abstract Genomic imprinting is the phenomena that leads to silencing of one copy of a gene inherited from a specific parent. Mutations in imprinted regions have been involved in diseases showing parent of origin effects. Identifying genes with evidence of parent of origin expression patterns in family studies allows the detection of more subtle imprinting. Here, we use allele specific expression in lymphoblastoid cell lines from 306 Hutterites related in a single pedigree to provide formal evidence for parent of origin effects. We take advantage of phased genotype data to assign parent of origin to RNA-seq reads in individuals with gene expression data. Our approach identified known imprinted genes, two putative novel imprinted genes, PXDC1 and PWAR6, and 14 genes with asymmetrical parent of origin gene expression. We used gene expression in peripheral blood leukocytes (PBL) to validate our findings, and then confirmed imprinting control regions (ICRs) using DNA methylation levels in the PBLs.
    MeSH term(s) Cell Line ; DNA Methylation ; Ethnicity/genetics ; Female ; Founder Effect ; Gene Expression ; Gene Expression Profiling ; Genomic Imprinting ; Haplotypes ; Humans ; Lymphocytes/metabolism ; Male ; Pedigree ; Polymorphism, Single Nucleotide ; Sequence Analysis, RNA
    Language English
    Publishing date 2018-09-11
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2267670-3
    ISSN 1932-6203 ; 1932-6203
    ISSN (online) 1932-6203
    ISSN 1932-6203
    DOI 10.1371/journal.pone.0203906
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: T-cell phenotypes are associated with serum IgE levels in Amish and Hutterite children.

    Hrusch, Cara L / Stein, Michelle M / Gozdz, Justyna / Holbreich, Mark / von Mutius, Erika / Vercelli, Donata / Ober, Carole / Sperling, Anne I

    The Journal of allergy and clinical immunology

    2019  Volume 144, Issue 5, Page(s) 1391–1401.e10

    Abstract: Objectives: Amish children raised on traditional farms have lower atopy and asthma risk than Hutterite children raised on modern farms. In our previous study we established that the Amish environment affects the innate immune response to decrease asthma ...

    Abstract Objectives: Amish children raised on traditional farms have lower atopy and asthma risk than Hutterite children raised on modern farms. In our previous study we established that the Amish environment affects the innate immune response to decrease asthma and atopy risk. Here we investigated T-cell phenotypes in the same Amish and Hutterite children as in our earlier study to elucidate how this altered innate immunity affects adaptive T cells.
    Methods: Blood was collected from 30 Amish and 30 Hutterite age- and sex-matched children; cells were cryopreserved until analysis. Flow cytometry was used to analyze cell subsets. Atopy was determined based on allergen-specific and total IgE levels.
    Results: Children exposed to Amish farms had increased activated regulatory CD4
    Conclusion: Amish children's blood leukocytes are not only altered in their innate immune status but also have distinct T-cell phenotypes that are often associated with increased antigen exposure.
    MeSH term(s) Adaptive Immunity ; Adolescent ; Allergens/immunology ; Amish ; Cells, Cultured ; Child ; Environmental Exposure/adverse effects ; Ethnic Groups ; Female ; Humans ; Hypersensitivity, Immediate/immunology ; Immunoglobulin E/blood ; Immunophenotyping ; Male ; Phenotype ; T-Lymphocyte Subsets/immunology ; T-Lymphocytes/immunology ; Tumor Necrosis Factor alpha-Induced Protein 3/genetics ; Tumor Necrosis Factor alpha-Induced Protein 3/metabolism
    Chemical Substances Allergens ; Immunoglobulin E (37341-29-0) ; TNFAIP3 protein, human (EC 3.4.19.12) ; Tumor Necrosis Factor alpha-Induced Protein 3 (EC 3.4.19.12)
    Language English
    Publishing date 2019-08-08
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 121011-7
    ISSN 1097-6825 ; 1085-8725 ; 0091-6749
    ISSN (online) 1097-6825 ; 1085-8725
    ISSN 0091-6749
    DOI 10.1016/j.jaci.2019.07.034
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Asthma-associated genetic variants induce IL33 differential expression through an enhancer-blocking regulatory region.

    Aneas, Ivy / Decker, Donna C / Howard, Chanie L / Sobreira, Débora R / Sakabe, Noboru J / Blaine, Kelly M / Stein, Michelle M / Hrusch, Cara L / Montefiori, Lindsey E / Tena, Juan / Magnaye, Kevin M / Clay, Selene M / Gern, James E / Jackson, Daniel J / Altman, Matthew C / Naureckas, Edward T / Hogarth, Douglas K / White, Steven R / Gomez-Skarmeta, Jose Luis /
    Schoetler, Nathan / Ober, Carole / Sperling, Anne I / Nóbrega, Marcelo A

    Nature communications

    2021  Volume 12, Issue 1, Page(s) 6115

    Abstract: Genome-wide association studies (GWAS) have implicated the IL33 locus in asthma, but the underlying mechanisms remain unclear. Here, we identify a 5 kb region within the GWAS-defined segment that acts as an enhancer-blocking element in vivo and in vitro. ...

    Abstract Genome-wide association studies (GWAS) have implicated the IL33 locus in asthma, but the underlying mechanisms remain unclear. Here, we identify a 5 kb region within the GWAS-defined segment that acts as an enhancer-blocking element in vivo and in vitro. Chromatin conformation capture showed that this 5 kb region loops to the IL33 promoter, potentially regulating its expression. We show that the asthma-associated single nucleotide polymorphism (SNP) rs1888909, located within the 5 kb region, is associated with IL33 gene expression in human airway epithelial cells and IL-33 protein expression in human plasma, potentially through differential binding of OCT-1 (POU2F1) to the asthma-risk allele. Our data demonstrate that asthma-associated variants at the IL33 locus mediate allele-specific regulatory activity and IL33 expression, providing a mechanism through which a regulatory SNP contributes to genetic risk of asthma.
    MeSH term(s) Alleles ; Animals ; Asthma/genetics ; Asthma/metabolism ; Chromatin/genetics ; Chromatin/metabolism ; Enhancer Elements, Genetic ; Female ; Genetic Predisposition to Disease ; Humans ; Interleukin-33/genetics ; Interleukin-33/metabolism ; Male ; Mice, Transgenic ; Octamer Transcription Factor-1/genetics ; Octamer Transcription Factor-1/metabolism ; Polymorphism, Single Nucleotide ; Promoter Regions, Genetic ; Zebrafish
    Chemical Substances Chromatin ; Interleukin-33 ; Octamer Transcription Factor-1
    Language English
    Publishing date 2021-10-21
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-021-26347-z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: A decade of research on the 17q12-21 asthma locus: Piecing together the puzzle.

    Stein, Michelle M / Thompson, Emma E / Schoettler, Nathan / Helling, Britney A / Magnaye, Kevin M / Stanhope, Catherine / Igartua, Catherine / Morin, Andréanne / Washington, Charles / Nicolae, Dan / Bønnelykke, Klaus / Ober, Carole

    The Journal of allergy and clinical immunology

    2018  Volume 142, Issue 3, Page(s) 749–764.e3

    Abstract: Chromosome 17q12-21 remains the most highly replicated and significant asthma locus. Genotypes in the core region defined by the first genome-wide association study correlate with expression of 2 genes, ORM1-like 3 (ORMDL3) and gasdermin B (GSDMB), ... ...

    Abstract Chromosome 17q12-21 remains the most highly replicated and significant asthma locus. Genotypes in the core region defined by the first genome-wide association study correlate with expression of 2 genes, ORM1-like 3 (ORMDL3) and gasdermin B (GSDMB), making these prime candidate asthma genes, although recent studies have implicated gasdermin A (GSDMA) distal to and post-GPI attachment to proteins 3 (PGAP3) proximal to the core region as independent loci. We review 10 years of studies on the 17q12-21 locus and suggest that genotype-specific risks for asthma at the proximal and distal loci are not specific to early-onset asthma and mediated by PGAP3, ORMDL3, and/or GSDMA expression. We propose that the weak and inconsistent associations of 17q single nucleotide polymorphisms with asthma in African Americans is due to the high frequency of some 17q alleles, the breakdown of linkage disequilibrium on African-derived chromosomes, and possibly different early-life asthma endotypes in these children. Finally, the inconsistent association between asthma and gene expression levels in blood or lung cells from older children and adults suggests that genotype effects may mediate asthma risk or protection during critical developmental windows and/or in response to relevant exposures in early life. Thus studies of young children and ethnically diverse populations are required to fully understand the relationship between genotype and asthma phenotype and the gene regulatory architecture at this locus.
    MeSH term(s) Asthma/ethnology ; Asthma/genetics ; Chromatin ; Chromosomes, Human, Pair 17 ; DNA Methylation ; Humans ; Phenotype ; Quantitative Trait Loci
    Chemical Substances Chromatin
    Language English
    Publishing date 2018-01-04
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 121011-7
    ISSN 1097-6825 ; 1085-8725 ; 0091-6749
    ISSN (online) 1097-6825 ; 1085-8725
    ISSN 0091-6749
    DOI 10.1016/j.jaci.2017.12.974
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  10. Article ; Online: Coexpression of spectrally distinct rhodopsins in Aedes aegypti R7 photoreceptors.

    Hu, Xiaobang / Whaley, Michelle A / Stein, Michelle M / Mitchell, Bronwen E / O'Tousa, Joseph E

    PloS one

    2011  Volume 6, Issue 8, Page(s) e23121

    Abstract: The retina of the mosquito Aedes aegypti can be divided into four regions based on the non-overlapping expression of a UV sensitive Aaop8 rhodopsin and a long wavelength sensitive Aaop2 type rhodopsin in the R7 photoreceptors. We show here that another ... ...

    Abstract The retina of the mosquito Aedes aegypti can be divided into four regions based on the non-overlapping expression of a UV sensitive Aaop8 rhodopsin and a long wavelength sensitive Aaop2 type rhodopsin in the R7 photoreceptors. We show here that another rhodopsin, Aaop9, is expressed in all R7 photoreceptors and a subset of R8 photoreceptors. In the dorsal region, Aaop9 is expressed in both the cell body and rhabdomere of R7 and R8 cells. In other retinal regions Aaop9 is expressed only in R7 cells, being localized to the R7 rhabdomere in the central and ventral regions and in both the cell body and rhabdomere within the ventral stripe. Within the dorsal-central transition area ommatidia do not show a strict pairing of R7-R8 cell types. Thus, Aaop9 is coexpressed in the two classes of R7 photoreceptors previously distinguished by the non-overlapping expression of Aaop8 and Aaop2 rhodopsins. Electroretinogram analysis of transgenic Drosophila shows that Aaop9 is a short wavelength rhodopsin with an optimal response to 400-450 nm light. The coexpressed Aaop2 rhodopsin has dual wavelength sensitivity of 500-550 nm and near 350 nm in the UV region. As predicted by the spectral properties of each rhodopsin, Drosophila photoreceptors expressing both Aaop9 and Aaop2 rhodopsins exhibit a uniform sensitivity across the broad 350-550 nm light range. We propose that rhodopsin coexpression is an adaptation within the R7 cells to improve visual function in the low-light environments in which Ae. aegypti is active.
    MeSH term(s) Aedes/cytology ; Aedes/genetics ; Aedes/metabolism ; Amino Acid Sequence ; Animals ; Animals, Genetically Modified ; Blotting, Western ; Drosophila/cytology ; Drosophila/genetics ; Drosophila/metabolism ; Fluorescent Antibody Technique ; Molecular Sequence Data ; Photoreceptor Cells, Invertebrate/cytology ; Photoreceptor Cells, Invertebrate/metabolism ; Protein Isoforms/genetics ; Protein Isoforms/metabolism ; Retina/cytology ; Retina/metabolism ; Rhodopsin/genetics ; Rhodopsin/metabolism ; Species Specificity ; Spectrophotometry
    Chemical Substances Protein Isoforms ; Rhodopsin (9009-81-8)
    Language English
    Publishing date 2011-08-08
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0023121
    Database MEDical Literature Analysis and Retrieval System OnLINE

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